This invention relates to 8-substituted 7-phenyl-1,2,4-triazolo[2,3-c]pyrimidine-5-amines and amides and the process for their preparation. More particularly, this invention provides new, useful and unobvious chemical compounds of formula I, useful as diuretics.
Diuretics are drugs used to increase the volume of urine excreted by the kidneys. They are employed principally for the relief of edema and ascites. These conditions occur in diseases of the heart, kidneys and liver. Diuretics are most effective in the treatment of cardiac edema, particularly that associated with congestive heart failure. They are also used in the ascites of cirrhosis, the nephrotic syndrome, diabetes insipidus, hypertension, edema of pregnancy, and to reduce cerebrospinal and intraocular fluid pressure. Some diuretics have highly specialized uses in glaucoma, hyperpotassemia, bromide intoxication, anginal syndrome, epilepsy, migraine, hypertension, and in premenstrual depression, conditions in which edema is not present or at least not definitely established.
The formation of urine from the blood, in simplest terms, consists of glomerular filtration and selective tubular reabsorption and secretion. As the glomerular filtrate passes through the tubules, substances essential to the blood and tissues--water, glucose, salts, and amino acids--are reabsorbed. Other substances in the glomerular filtrate, such as urea, are not as readily absorbed by the tubules. Thus, it is thought that in the renal tubule there is a specific mechanism for the transport of each ionic species, the capacities of which are quite different. For example, the capacity of the renal tubule to reabsorb sulfate ion is limited. The tubular capacity for the reabsorption of phosphate is such that sufficient is reabsorbed to maintain the normal extracellular level and any excess is excreted. On the other hand, much larger amounts of bicarbonate ion and chloride ion can be reabsorbed.
Thiazide diuretics act mainly to block sodium and chloride reabsorption at the first (thick) portion of the distal tubule. They also have a mild anti-carbonic anhydrase effect. The resulting natriuresis is accompanied by increased excretion of potassium, bicarbonate, chloride and water.
The antihypertensive action of the thiazides is attributable to two factors: (a) depletion of sodium and subsequent reduction in plasma volume and (2) a decrease in peripheral resistance. The latter is thought to be due either to the loss of sodium from the arteriolar wall or a direct action on the vascular bed. In addition, there is some inhibition of the pressor activity of norepinephrine. Quantitative hypersensitivity to diuretics is frequently encountered. Also possible is potassium deficiency pancreatitis, decreased glucose tolerance, increased uric acid levels and increased anticoagulent effect.